INFLAMMATION AIRWAYS REACTIVITY AND ASTHMA

这个项目的中心假设是 受试者中存在由T细胞协调的免疫调节 导致哮喘，并导致呼吸道内的炎症反应。在……里面 此外，T细胞衍生的不利影响的关键靶点 细胞因子是糖皮质激素受体，也是神经分子 以及呼吸道内的平滑肌肉。解决这些问题的研究以及 其他假设将在人类和动物模型中进行 代表多个学科的调查人员并利用 肺生理学和免疫学技术以及 分子和细胞生物学。在临床研究中， 导致激素抵抗型哮喘的机制将是 已定义。作为这项工作的一部分，假设抗原 触发IL-2和IL-4选择性扩增分泌Vbeta8+T细胞 诱导糖皮质激素受体配体结合的细胞 DNA结合缺陷将得到解决。假设 夜间哮喘患者的反馈功能异常 涉及促肾上腺皮质激素释放激素的机制 降低炎症反应的过程将被研究。预赛 夜间哮喘患者外周血T细胞降低的观察 淋巴细胞糖皮质激素受体结合亲和力即 夜间被夸大的将被检查以确定受试者是否患有 最低的受体结合亲和力也有最大的mrna。 IL-2和IL-4在活检标本中的表达利用模型 为了解决人类无法接受的假设， T淋巴细胞和IgE抗体在改变呼吸道功能中的作用 在正常和基因敲除小鼠的过敏原驱动模型中 已定义。涉及免疫细胞和/或 不同同位素的过敏原特异性单抗的输注 抗体将被用来解决它们在改变呼吸道中的作用 功能。此外，细胞和生化机制 对过敏原引起的胆碱能输入增加负责 进入呼吸道(神经末梢释放更多的乙酰胆碱) 以及由神经调节的呼吸道功能丧失 松弛通路(非肾上腺素能非胆碱能抑制[NANCI] 系统)将被定义。环状3‘，5’-腺苷的变化 单磷酸途径，可能是T细胞细胞因子诱导的 过敏原致敏和挑战的结果将在#年进行评估 南希反应的研究。该计划将提供额外的 对呼吸道炎症和炎症机制的洞察 高反应性。

The central hypothesis of this program is that abnormalities in immune regulation orchestrated by T cells are present in subjects with asthma and lead to inflammatory responses within airways. In addition, critical targets adversely affected by T cell derived cytokines are glucocorticoid receptors as well as neural elements and smooth muscle within airways. Studies that address these and other hypotheses will be conducted in man and animal models by investigators representing multiple disciplines and employing the techniques of pulmonary physiology and immunology as well as molecular and cellular biology. In clinical studies, the mechanisms responsible for corticosteroid resistant asthma will be defined. As part of this work, the hypothesis that antigens trigger selective expansion of IL-2 and IL-4 secreting Vbeta8+T cells that induce a combination of glucocorticoid receptor ligand and DNA binding defects will be addressed. The hypothesis that patients with nocturnal asthma have an abnormality in feedback mechanisms involving corticotropin releasing hormone that normally decrease the inflammatory process will be studied. The preliminary observation that subjects with nocturnal asthma have decreased T lymphocyte glucocorticoid receptor binding affinity that is exaggerated at night will be examined to determine if subjects with the lowest receptor binding affinity also have the greatest mRNA expression of IL-2 and IL-4 in biopsy specimens. Utilizing models to address hypotheses that cannot be entertained in humans, the role of T lymphocytes and IgE antibody in altering airway function in allergen-driven models in normal and knockout mice will be defined. Studies involving transfer of immune cells and/or infusions of various isotopes of allergen-specific monoclonal antibodies will be used to address their role in altering airway function. In addition, the cellular and biochemical mechanisms responsible for allergen induced increases in cholinergic input into airways (greater release of acetylcholine from nerve endings) as well as the functional loss of the airways' neurally mediated relaxant pathway (nonadrenergic noncholinergic inhibitory [NANCi] system) will be defined. Changes in the cyclic 3',5'-adenosine monophosphate pathway that may be T cell cytokine-induced as a result of allergen sensitization and challenge will be assessed in study of NANCi responses. This program will provide additional insight into mechanisms responsible for airways inflammation and hyperresponsiveness.